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Protein

Tribbles homolog 3

Gene

TRIB3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Disrupts insulin signaling by binding directly to Akt kinases and blocking their activation. May bind directly to and mask the 'Thr-308' phosphorylation site in AKT1. Binds to ATF4 and inhibits its transcriptional activation activity. Interacts with the NF-kappa-B transactivator p65 RELA and inhibits its phosphorylation and thus its transcriptional activation activity. Interacts with MAPK kinases and regulates activation of MAP kinases. May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells. Does not display kinase activity. Inhibits the transcriptional activity of DDIT3/CHOP and is involved in DDIT3/CHOP-dependent cell death during ER stress. Can inhibit APOBEC3A editing of nuclear DNA.5 Publications

GO - Molecular functioni

  • ATP binding Source: InterPro
  • mitogen-activated protein kinase kinase binding Source: GO_Central
  • protein kinase binding Source: UniProtKB
  • protein kinase inhibitor activity Source: UniProtKB-KW
  • transcription corepressor activity Source: UniProtKB
  • ubiquitin protein ligase binding Source: BHF-UCL
  • ubiquitin-protein transferase regulator activity Source: BHF-UCL

GO - Biological processi

  • cellular response to insulin stimulus Source: BHF-UCL
  • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: UniProtKB
  • negative regulation of fat cell differentiation Source: BHF-UCL
  • negative regulation of fatty acid biosynthetic process Source: BHF-UCL
  • negative regulation of protein kinase activity Source: BHF-UCL
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: ParkinsonsUK-UCL
  • positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: GO_Central
  • positive regulation of protein binding Source: BHF-UCL
  • positive regulation of ubiquitin-protein transferase activity Source: BHF-UCL
  • protein phosphorylation Source: InterPro
  • regulation of glucose transport Source: BHF-UCL
  • regulation of MAP kinase activity Source: UniProtKB
  • response to endoplasmic reticulum stress Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Protein kinase inhibitor

Keywords - Biological processi

Apoptosis, Stress response, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-165158. Activation of AKT2.
R-HSA-1989781. PPARA activates gene expression.
R-HSA-199418. Negative regulation of the PI3K/AKT network.
R-HSA-389357. CD28 dependent PI3K/Akt signaling.
R-HSA-5218920. VEGFR2 mediated vascular permeability.
SignaLinkiQ96RU7.
SIGNORiQ96RU7.

Names & Taxonomyi

Protein namesi
Recommended name:
Tribbles homolog 3
Short name:
TRB-3
Alternative name(s):
Neuronal cell death-inducible putative kinase
SINK
p65-interacting inhibitor of NF-kappa-B
Gene namesi
Name:TRIB3
Synonyms:C20orf97, NIPK, SKIP3, TRB3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

HGNCiHGNC:16228. TRIB3.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA25804.

Polymorphism and mutation databases

BioMutaiTRIB3.
DMDMi28201830.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 358358Tribbles homolog 3PRO_0000131866Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei12 – 121PhosphoserineCombined sources

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ96RU7.
MaxQBiQ96RU7.
PaxDbiQ96RU7.
PeptideAtlasiQ96RU7.
PRIDEiQ96RU7.

PTM databases

iPTMnetiQ96RU7.
PhosphoSiteiQ96RU7.

Expressioni

Tissue specificityi

Highest expression in liver, pancreas, peripheral blood leukocytes and bone marrow. Also highly expressed in a number of primary lung, colon and breast tumors. Expressed in spleen, thymus, and prostate and is undetectable in other examined tissues, including testis, ovary, small intestine, colon, leukocyte, heart, brain, placenta, lung, skeletal muscle, and kidney.3 Publications

Inductioni

By hypoxia, TNF, and by nutrient starvation. Expression is PI 3-kinase and/or NF-kappa-B-dependent. Induced by ER stress via ATF4-DDIT3/CHOP pathway and can downregulate its own induction by repression of ATF4-DDIT3/CHOP functions.4 Publications

Gene expression databases

BgeeiENSG00000101255.
CleanExiHS_TRIB3.
ExpressionAtlasiQ96RU7. baseline and differential.
GenevisibleiQ96RU7. HS.

Organism-specific databases

HPAiHPA015272.

Interactioni

Subunit structurei

Interacts with AKT1, AKT2, ATF4, MAP2K1 and MAP2K7. Interacts with DDIT3/CHOP and inhibits its interaction with EP300/P300. Interacts (via N-terminus) with APOBEC3A. Interacts with APOBEC3C.6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ATF4P188485EBI-492476,EBI-492498
ATF4Q96AQ34EBI-492476,EBI-740263
PRMT5O147442EBI-492476,EBI-351098
RPGRIP1Q96KN73EBI-492476,EBI-1050213

GO - Molecular functioni

  • mitogen-activated protein kinase kinase binding Source: GO_Central
  • protein kinase binding Source: UniProtKB
  • ubiquitin protein ligase binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi121756. 36 interactions.
IntActiQ96RU7. 16 interactions.
MINTiMINT-1384866.
STRINGi9606.ENSP00000217233.

Structurei

3D structure databases

ProteinModelPortaliQ96RU7.
SMRiQ96RU7. Positions 72-353.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini68 – 316249Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 127127Interaction with DDIT3/CHOPAdd
BLAST

Domaini

The protein kinase domain is predicted to be catalytically inactive.

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0583. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00840000129780.
HOGENOMiHOG000231872.
HOVERGENiHBG067729.
InParanoidiQ96RU7.
KOiK19518.
PhylomeDBiQ96RU7.
TreeFamiTF329785.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR024104. Tribbles/Ser_Thr_kinase_40.
IPR024106. Tribbles_TRB3.
[Graphical view]
PANTHERiPTHR22961. PTHR22961. 1 hit.
PTHR22961:SF14. PTHR22961:SF14. 1 hit.
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q96RU7-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRATPLAAPA GSLSRKKRLE LDDNLDTERP VQKRARSGPQ PRLPPCLLPL
60 70 80 90 100
SPPTAPDRAT AVATASRLGP YVLLEPEEGG RAYQALHCPT GTEYTCKVYP
110 120 130 140 150
VQEALAVLEP YARLPPHKHV ARPTEVLAGT QLLYAFFTRT HGDMHSLVRS
160 170 180 190 200
RHRIPEPEAA VLFRQMATAL AHCHQHGLVL RDLKLCRFVF ADRERKKLVL
210 220 230 240 250
ENLEDSCVLT GPDDSLWDKH ACPAYVGPEI LSSRASYSGK AADVWSLGVA
260 270 280 290 300
LFTMLAGHYP FQDSEPVLLF GKIRRGAYAL PAGLSAPARC LVRCLLRREP
310 320 330 340 350
AERLTATGIL LHPWLRQDPM PLAPTRSHLW EAAQVVPDGL GLDEAREEEG

DREVVLYG
Length:358
Mass (Da):39,578
Last modified:February 1, 2003 - v2
Checksum:iCE15FD89A81E8D63
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti24 – 241N → D in CAG33647 (Ref. 7) Curated
Sequence conflicti105 – 1051L → P in BAB15597 (PubMed:14702039).Curated
Sequence conflicti105 – 1051L → P in BAD96557 (Ref. 8) Curated
Sequence conflicti114 – 1141L → V in AAK58175 (PubMed:15299019).Curated
Sequence conflicti194 – 1952ER → DREK in AAK58175 (PubMed:15299019).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti60 – 601T → I in a glioblastoma multiforme sample; somatic mutation. 1 Publication
Corresponds to variant rs757496714 [ dbSNP | Ensembl ].
VAR_042372
Natural varianti84 – 841Q → R.2 Publications
Corresponds to variant rs2295490 [ dbSNP | Ensembl ].
VAR_023965
Natural varianti153 – 1531R → H.1 Publication
Corresponds to variant rs35051116 [ dbSNP | Ensembl ].
VAR_042373
Natural varianti274 – 2741R → H.1 Publication
Corresponds to variant rs56291463 [ dbSNP | Ensembl ].
VAR_042374
Natural varianti347 – 3471E → K.1 Publication
Corresponds to variant rs56342286 [ dbSNP | Ensembl ].
VAR_042375

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250311 mRNA. Translation: AAK58175.1.
AJ697936 mRNA. Translation: CAG27047.1.
AY247738 mRNA. Translation: AAP04407.1.
AK026945 mRNA. Translation: BAB15597.1.
CR457366 mRNA. Translation: CAG33647.1.
AK222837 mRNA. Translation: BAD96557.1.
AL034548 Genomic DNA. Translation: CAB81634.1.
BC019363 mRNA. Translation: AAH19363.1.
BC027484 mRNA. Translation: AAH27484.1.
CCDSiCCDS12997.1.
RefSeqiNP_001288117.1. NM_001301188.1.
NP_001288119.1. NM_001301190.1.
NP_001288122.1. NM_001301193.1.
NP_001288125.1. NM_001301196.1.
NP_001288130.1. NM_001301201.1.
NP_066981.2. NM_021158.4.
UniGeneiHs.516826.

Genome annotation databases

EnsembliENST00000217233; ENSP00000217233; ENSG00000101255.
GeneIDi57761.
KEGGihsa:57761.
UCSCiuc002wdm.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250311 mRNA. Translation: AAK58175.1.
AJ697936 mRNA. Translation: CAG27047.1.
AY247738 mRNA. Translation: AAP04407.1.
AK026945 mRNA. Translation: BAB15597.1.
CR457366 mRNA. Translation: CAG33647.1.
AK222837 mRNA. Translation: BAD96557.1.
AL034548 Genomic DNA. Translation: CAB81634.1.
BC019363 mRNA. Translation: AAH19363.1.
BC027484 mRNA. Translation: AAH27484.1.
CCDSiCCDS12997.1.
RefSeqiNP_001288117.1. NM_001301188.1.
NP_001288119.1. NM_001301190.1.
NP_001288122.1. NM_001301193.1.
NP_001288125.1. NM_001301196.1.
NP_001288130.1. NM_001301201.1.
NP_066981.2. NM_021158.4.
UniGeneiHs.516826.

3D structure databases

ProteinModelPortaliQ96RU7.
SMRiQ96RU7. Positions 72-353.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121756. 36 interactions.
IntActiQ96RU7. 16 interactions.
MINTiMINT-1384866.
STRINGi9606.ENSP00000217233.

PTM databases

iPTMnetiQ96RU7.
PhosphoSiteiQ96RU7.

Polymorphism and mutation databases

BioMutaiTRIB3.
DMDMi28201830.

Proteomic databases

EPDiQ96RU7.
MaxQBiQ96RU7.
PaxDbiQ96RU7.
PeptideAtlasiQ96RU7.
PRIDEiQ96RU7.

Protocols and materials databases

DNASUi57761.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000217233; ENSP00000217233; ENSG00000101255.
GeneIDi57761.
KEGGihsa:57761.
UCSCiuc002wdm.4. human.

Organism-specific databases

CTDi57761.
GeneCardsiTRIB3.
HGNCiHGNC:16228. TRIB3.
HPAiHPA015272.
MIMi607898. gene.
neXtProtiNX_Q96RU7.
PharmGKBiPA25804.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0583. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00840000129780.
HOGENOMiHOG000231872.
HOVERGENiHBG067729.
InParanoidiQ96RU7.
KOiK19518.
PhylomeDBiQ96RU7.
TreeFamiTF329785.

Enzyme and pathway databases

ReactomeiR-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-165158. Activation of AKT2.
R-HSA-1989781. PPARA activates gene expression.
R-HSA-199418. Negative regulation of the PI3K/AKT network.
R-HSA-389357. CD28 dependent PI3K/Akt signaling.
R-HSA-5218920. VEGFR2 mediated vascular permeability.
SignaLinkiQ96RU7.
SIGNORiQ96RU7.

Miscellaneous databases

ChiTaRSiTRIB3. human.
GeneWikiiTRIB3.
GenomeRNAii57761.
PROiQ96RU7.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000101255.
CleanExiHS_TRIB3.
ExpressionAtlasiQ96RU7. baseline and differential.
GenevisibleiQ96RU7. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR024104. Tribbles/Ser_Thr_kinase_40.
IPR024106. Tribbles_TRB3.
[Graphical view]
PANTHERiPTHR22961. PTHR22961. 1 hit.
PTHR22961:SF14. PTHR22961:SF14. 1 hit.
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTRIB3_HUMAN
AccessioniPrimary (citable) accession number: Q96RU7
Secondary accession number(s): Q53GU4
, Q53ZW7, Q6I9Y9, Q8TAI6, Q9H5M8, Q9NUD2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 2003
Last sequence update: February 1, 2003
Last modified: September 7, 2016
This is version 149 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Caution

The role of this protein in Akt activation has been demonstrated by Du et al (PubMed:12791994) for the mouse ortholog but Iynedjian (PubMed:15469416) has not been able to reproduce the result in rat hepatocytes.Curated

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.